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Publication numberUS4915940 A
Publication typeGrant
Application numberUS 07/271,304
Publication dateApr 10, 1990
Filing dateNov 15, 1988
Priority dateDec 8, 1987
Fee statusPaid
Also published asDE3869355D1, EP0319964A1, EP0319964B1
Publication number07271304, 271304, US 4915940 A, US 4915940A, US-A-4915940, US4915940 A, US4915940A
InventorsIzumi Saitoh, Kaori Ikeda, Yoshio Doi, Shohei Egawa
Original AssigneeShionogi & Co., Ltd.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Film-formation-type antifungal preparation
US 4915940 A
Abstract
Film-formation-type antifungal preparations for external application, consisting essentially of about 0.1% to about 1.5% of tolnaphtate, about 10% to about 20% of a dimethylaminoethyl methacrylate-methacrylic acid ester copolymer and 0.5% to about 10% of a medium chain fatty acid ester in an alcoholic solvent but containing practically no water.
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Claims(5)
What is claimed is:
1. A film-formation-antifungal preparation consisting essentially of about 0.1% to about 1.5% of tolnapbtate. about 10% to about 20% of a dimethylaminoethyl methacrylate-methacrylic acid ester copolymer, and 0.5% to about 10% of a medium chain fatty acid ester in an alcoholic solvent but containing practically no water.
2. The film-formation-antifungal preparation claimed in claim 1, wherein said medium chain fatty acid ester is tetraglyceryl monocaprate.
3. The film-formation-antifungal preparation claimed in claim 1, further containing about 0.1% to about 5% of a thickening agent.
4. The film-formation-antifungal preparation claimed in claim 1, wherein said alcoholic solvent is ethanol or isopropanol.
5. The film-formation-antifungal preparation claimed in claim 3, wherein said thickening agent is cthyl cellulose, hydroxypropyl cellulose, or hydroxypropylmethyl cellulose.
Description
BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention relates to preparations for topical application which contain tolnaphtate (hereinafter abbreviated as TOL) known as an antifungal agent. More specifically the Preparations of this invention are so designed as to form a flexible, strong, transparent film on the skin and gradually release TOL therefrom.

2. Prior Art

So far, tinctures, creams, gels, or the like preparations have been used for the topical treatment of mycosis.

TOL bas a potent action against fungi, especially against Trychophytons and therefore, it has long been used for the treatment of tinea pedis. However. in many cases, mycosis as represented by athlete's foot primarily occurs at moist Parts of the body. So, when an ointment or a gel preparation is applied to the affected part, it makes the affected part even more moist, thereby giving a strange feeling or staining clothing. These are shortcomings in using ointments or gel preparations. A tincture has such shortcomings as to take longer time to dry on the parts of the body to which it is applied. Furthermore it has been another shortcoming that conventional TOL-preparations result in TOL becoming crystallized in storage or when applied because of its property of being hardly soluble in most solvents.

SUMMARY OF THE INVENTION

The present invention provides film-formation-type anti-fungal preparations for topical application, consisting essentially of about 0.1% to about 1.5% of tolnaphtate, about 10% to about 20% of a dimethylaminoethyl methacrylate-methacrylic acid ester copolymer (hereinafter abbreviated as DMMA-MA), and 0.5% to about 10% of a medium chain fatty acid ester in an alcoholic solvent but containing practically no water.

BRIEF DESCRIPTION OF THE DRAWING

The ordinate shows TOL amount in the skin, while the abscissa shows time. The remaining amounts of TOL in the skin are shown by the mark " ○" for the control and by the mark " ○" for the Example 1 preparation disclosed below.

DESCRIPTION OF THE PREFERRED EMBODIMENT Problems to be Solved

In view of the Problem above the present inventors tried to find such base ingredients as to prevent TOL from crystallization in storage or even after application, and as to enhance transdermal absorbability of TOL and, consequently, they have completed the present invention. The preparations of this invention enhance and sustain the action of TOL and, therefore, they are expected to give an excellent efficacy in a once-a-day application.

The preparations of this invention are capable of forming a flexible strong film on the skin when applied and of keeping the drug effect for a long period of time. Proportions used in this invention are shown as percentage by weight (w/w %) of certain additive to the total weight of the whole preparation.

Means to Solve the Problem

This invention can be achieved by dissolving about 0.1%-- about 1.5% of TOL, about 10%--about 20% of DMMA-MA, and 0.5% --about 10% of a medium chain fatty acid ester in an alcoholic solvent. If necessary, about 0.1% --about 2.5% of a thickening agent and/or a plasticizer may be further added.

lOL used in this invention is a potent antifugal agent and very popular as cream- or gel-preparations. Eudragit® E100 may be a good representative for DMMA-MA.

The medium chain fatty acid ester includes glyceryl monocaprate (GMC). tetraglyceryl monocaprate (TGMC), propyleneglycol dicaprate (PGDC), tetraglyceryl hexacaprate (TGHC), and the like. TGMC is especially preferred.

The aqueous alcohol used in this invention means such a dry lower alkanol as to contain substantially no water. Lower alkanol includes ethanol, propanol, isopropanol, and the like.

Thickening agents including cellulose derivatives such as ethyl cellulose (EC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), and the like are preferably used. Plasticizers including propylene glycol (PG), polyethylene glycol (PEG), and the like are preferably used.

The tinea pedis preparations of this invention are remarkably improved in enhancing the transdermal absorbability of TOL and in making drug effectiveness last for a long time as compared with conventional preparations, creams, gels, tinctures or the like. So, it can be expected that once-a-day application of the preparation is enough to attain good efficacy. The present invention is explained in more detail in the following Examples and Experiments, which are not intended to limit the scope of the invention.

EXAMPLE 1

Isopropanol (76g) and 5g of TGMC were put in a closed type vessel equipped with a stirrer. DMMA-MA (15g; EUDRAGIT® E100) and 3g of EC were gradually added thereto to give a clear solution, to which 1g of TOL was dissolved with stirring to make the objective preparation (100 g) of this invention.

EXAMPLES 2 -4

In substantially the same manner as in Example 1, the following instant preparations for tinea pedis were obtained.

              TABLE 1______________________________________    Example      2         3      4       ControlComponents (%)       (%)    (%)     (%)______________________________________TOL         1         1      1       1DMMA-MA    15        15     15      15GMC         5TGMC                  5TGHC                         5PG                                   3Ethanol              79     79      81Isopropanol      79______________________________________
EXPERIMENT 1

The precipitation of crystals was examined to study shelf life stability on each of the following preparations. The e in solution and the presence of crystals were examined by observation with the eye or under a microscope.

Preparations Examined

Preparations manufactured in Examples 1 to 4

Control: Control preparation shown in Table 1

              TABLE 2______________________________________Stored at 5° C. in tightly closed container            After   After After After AfterPrepa-           1       2     1     2     3ration Initial   Week    Weeks Month Months                                      Months______________________________________1      --        --      --    --    --    --2      --        --      --    --    --    ○3      --        --      --    --    --    --4      --        --      --    --    --    --Control  --        --      ○______________________________________ (Remarks) --: No change in solution & no formation of crystals were observed.  ○ : Change in solution & formation of crystals were observed.
EXPERIMENT 2

The in vivo transdermal absorption study shown in the following experiments was carried out, basically according to the undermentioned method:

Test Method

1. Male Wister rats (9 weeks of age, n=5-8) anesthetised by urethane have their abdominal hair removed carefully with electric clippers and electric razor.

2. The rat is fixed on its back, and then an absorption chamber (application area: 10 cm2) is fixed on the surface of the hairless abdomen with an instant adhesive.

3. A pre-fixed dose of a test material (2 mg as TOL per rat) is placed into the chamber.

4. After a certain period of time, the coating film formed on the skin in the chamber is removed off with distilled water and collected into a suitable vessel.

5. The chamber is removed and the application area of the skin is cut off.

6. The sample in item 4 and the piece of the skin in Item 5 are employed for the TOL content measurement by HPLC.

Along the test method mentioned above, a comparative study for transdermal absorption of TOL was carried out on some instant preparations and a commercially available one. TOL amount in the skin 4 hours after application is as follows.

Result

              TABLE 3______________________________________        TOL Amount in the skinPreparation  (mcg/10 cm2)______________________________________Example 1    9.04 ± 2.50Example 2    3.97 ± 1.08Example 3    8.84 ± 2.85Example 4    6.21Commercially 0.54 ± 0.06Available______________________________________
Remarks

Commercially Available: Pasca® Gel (by Shionogi & Co., Ltd., containing 1% of TOL)

The instant preparations of this invention exhibit much her transdermal absorbabilities than the gel preparation commercially available one) which has generally been believed to exhibit: a high absorbability.

EXPERIMENT 3

TOL amounts in the skin were measured at several points of time for the preparation of Example 1 and a commercially available Preparation (1% Pasca® Gel: made-by Shionogi & Co., Ltd.), to evaluate substantiality of TOL.

Result

The result is shown in the drawing. As compared with the control the preparations of this invention were remarkably improved in the transdermal absorbability of TOL and, additionally, they are capable of keeping high TOL concentrations in the skin for a long period of time. Consequently, the preparation of this invention exhibits a much larger area under the curve (AUC), the fact of which demonstrates a high bioavailability of TOL.

From those results, it is expected that the tinea pedis preparations of this invention will give an excellent efficacy in the treatment at only a once-a-day application.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3989815 *Jun 19, 1975Nov 2, 1976Nelson Research & Development CompanyNovel N-bis-azacyclopentan-2-onyl alkanes
US4136162 *Dec 27, 1977Jan 23, 1979Schering AktiengesellschaftEasily cut unit dosage for enteral or topical administration
CA1136045A1 *May 21, 1980Nov 23, 1982Herbert StrickerTransdermal release system for pharmaceutical preparations
JPH08159425A * Title not available
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US5026554 *Sep 13, 1990Jun 25, 1991Merck & Co., Inc.Applying or administering fungicide
US5614178 *Jun 27, 1994Mar 25, 1997The Procter & Gamble CompanyCompositions for topical delivery of drugs comprising a mixture of high and low HLB surfactants and alkoxylated ether
US5707635 *May 25, 1994Jan 13, 1998Richardson-Vicks Inc.Containing a crosslinked polyacrylamide-type polymer and an active compound, optionally a humectant and an emollient
US5776485 *Jun 6, 1995Jul 7, 1998Richardson-Vicks Inc.Nonionic polyacrylamide with high molecular weight for drug delivery
US5874095 *Mar 27, 1998Feb 23, 1999Richardson-Vicks Inc.Pharmaceutical active material, non-ionic crosslinked polyacrylamide having a molecular weight of from 1,000,000 to 30,000,000, the polyacrylamide being predispersed in a water-immiscible oil containing a surfactant
US5922313 *Jan 30, 1998Jul 13, 1999Bio-Safe Enterprises, Inc.Lotion consists of a mixture of polyvinylpyrrolidone and hydroxyethyl cellulose, an antibacterial agent chlorhexidine digluconate or 2,4,4'-trichloro-2'-hydroxydiphenylether, blend of glyceryl stearate and polyethylene glycol emulsifer
US5989536 *Apr 9, 1996Nov 23, 1999The Procter & Gamble CompanyPersonal cleansing compositions containing alkoxylated ether and cationic ammonium salt for deposition of active agent upon the skin
US6214327Jul 12, 1999Apr 10, 2001Bio-Safe Enterprises, Inc.Antibacterial composition
US6277892Feb 4, 1994Aug 21, 2001Schering-Plough Healthcare Products, Inc.Topical composition comprising sunless tanning agent and high molecular weight crosslinked cationic polymer based on dialkylaminoalkyl (meth)acrylate monomer or its quaternary ammonium or acid addition salt
Classifications
U.S. Classification514/481, 424/404, 424/78.07, 424/409
International ClassificationA61P31/04, A61K9/70, A61P31/10, A61K31/27
Cooperative ClassificationA61K31/27, A61K9/7015
European ClassificationA61K31/27, A61K9/70D
Legal Events
DateCodeEventDescription
Sep 20, 2001FPAYFee payment
Year of fee payment: 12
May 14, 1997FPAYFee payment
Year of fee payment: 8
May 19, 1993FPAYFee payment
Year of fee payment: 4
Nov 15, 1988ASAssignment
Owner name: SHIONOGI & CO., LTD., 12, 3-CHOME, DOSHO-MACHI, HI
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:SAITOH, IZUMI;IKEDA, KAORI;DOI, YOSHIO;AND OTHERS;REEL/FRAME:004972/0987
Effective date: 19881017
Owner name: SHIONOGI & CO., LTD.,JAPAN
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SAITOH, IZUMI;IKEDA, KAORI;DOI, YOSHIO AND OTHERS;REEL/FRAME:4972/987
Owner name: SHIONOGI & CO., LTD., JAPAN
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SAITOH, IZUMI;IKEDA, KAORI;DOI, YOSHIO;AND OTHERS;REEL/FRAME:004972/0987